Composition and method for treatment of hepatic encephalopathy

ABSTRACT

The inventions provide an improved treatment for hepatic encephalopathy characterized by hyperammonemia and/or constipation, comprising the oral administration of polyethylene glycol (PEG) in amounts sufficient to reduce plasma levels of ammonia and/or to alleviate constipation. Preferably, the PEG is administered in combination with lactulose, which provides a palatable composition for the treatment of HE with excellent therapeutic benefits and reduced side effects as compared to lactulose alone.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 10/748,185, filed Dec. 31, 2003.

BACKGROUND OF THE INVENTION

1. Field of Art

Hepatic encephalopathy (HE) is a syndrome associated with liverdysfunction, characterized by a decline in mental function andneurological abnormalities. Distinctive clinical signs includepersonality changes and intellectual impairment, and neuromuscularanomalies such as asterixis (flapping tremor) and alterations in gait.

The syndrome typically manifests in patients with an extensivecollateral blood vessel system (extrahepatic portal shunts) whichdiverts portal venous blood away from the liver into the systemiccirculation. Thus, toxic metabolites absorbed into the bloodstream fromthe intestines may largely bypass the liver and enter the generalcirculatory system without being detoxified. Among other ramifications,such toxins can cause metabolic aberrations in the central nervoussystem (CNS) which lead to increased permeability of the blood-brainbarrier and increased transport of toxic substances across this barrierinto the brain. In addition to promoting permeability of the neuronalmembrane, high plasma levels of certain neurotoxins are thought tocontribute to changes in energy metabolism and nerve processes in thebrain. Neurotoxins which have been implicated in the pathogenesis ofhepatic encephalopathy include false neurotransmitters, mercaptans,γ-amino butyric acid, and ammonia.

Ammonia is normally produced in the gastrointestinal tract by bacterialdegradation of peptides and other nitrogen-containing compounds, andthen detoxified in the liver by conversion to urea and glutamine. If theliver is sufficiently diseased, or bypassed as when portal shunts arepresent, plasma levels of ammonia may increase to toxic levels,affecting, for example, the transport of amines, water, and electrolytesacross the neuronal membrane. While the role that ammonia plays in thepathogenesis of hepatic encephalopathy is not entirely clear, reductionof plasma levels of ammonia has been clinically observed to improve HEin many cases, and evaluation of ammonia blood levels for hyperammonemiais widely routine in suspected cases.

2. Discussion of Related Art

A common treatment of hyperammonemia in hepatic encephalopathy is theoral administration of lactulose, a disaccharide of fructose andgalactose. Lactulose is not metabolized by mammals and reaches the largeintestine substantially intact, where it is digested by residentmicroorganisms to produce organic acids (lactic, formic, acetic) andCO₂. High local concentrations of lactulose draw free ammonia insolution from the bloodstream into the bowel where it reacts with theseacids to form their ammonium salts which are then excreted.

In addition to ammonia detoxification in HE, lactulose additionallyfunctions as an osmotic laxative or stool softener by increasing gutsolute concentrations and drawing water into the large intestine. Asconstipation as well as hyperammonemia is a common condition in HE,lactulose is a significant therapy for patients. However, it is verydifficult to obtain compliance from patients for several reasons, mainlythat current lactulose formulations have a very bad taste, and that atthe required dosages they frequently cause bloating and nausea to thepoint of significant discomfort.

SUMMARY OF THE DISCLOSURE

The inventions provide an improved treatment for hepatic encephalopathycharacterized by hyperammonemia and/or constipation, comprising the oraladministration of polyethylene glycol (PEG) in amounts sufficient toreduce plasma levels of ammonia and/or to alleviate constipation.Preferably, the PEG is administered in combination with lactulose, whichprovides a palatable composition for the treatment of HE with excellenttherapeutic benefits and reduced side effects as compared to lactulosealone.

DETAILED DESCRIPTION OF THE INVENTIONS

As described at length in U.S. Pat. No. 5,710,183 issued 20 Jan. 1998 tothe present inventor, PEG has been used as an osmotic bowel cleanser orlaxative which draws water into the bowel, thereby increasing bowelmotility and softening the stool. The present inventions are predicatedon the discovery that the osmotic effects of PEG are useful not only forsoftening the stool and/or increasing bowel motility of constipated HEpatients, but also for inhibiting production of ammonia in the bowel ofpatients at risk of hyperammonemia by accelerating the passage ofproteins and other nitrogenous metabolites through the gastrointestinaltract. By reducing the residence time of ingested food in the digestivesystem, catabolism of metabolites yielding ammonia byproduct isminimized. The residence time can be managed by adjusting the PEG dosagefor the desired results; if, for example, a dietary overload of proteinhas precipitated or exacerbated an occurrence of HE, higher and/or morefrequent dosages of PEG which will induce at least moderate diarrhea tominimize protein digestion and the consequent production of ammonia, maybe desirable. In severe cases, one may want to use amounts of PEGsuitable for bowel cleansing, for example as set forth in U.S. Pat. No.5,710,183, incorporated herein by reference.

In a preferred embodiment, the invention comprises a composition of PEGand lactulose powder for the treatment of constipation and/orhyperammonemia in HE or other needy patients. This composition combinesthe osmotic properties of lactulose and PEG for laxative/stool softeningbenefits; additionally, these same osmotic properties increase the fluidvolume in the gut by drawing in liquid containing excess free ammonia,which facilitates conversion of this toxin to harmless ammonium salts inthe presence of endogenous bacteria and lactulose as detailed supra.Thus, lactulose both enhances the osmotic properties of the PEG andmediates detoxification of ammonia entering the intestine by osmosis.Further, the gas and cramping which frequently occurs with the use oflactulose alone for treating HE is significantly reduced, owing in partto the significantly lower dosage (½ to ⅓ the standard dose) usedherein. Importantly, compositions of the invention containing bothlactulose and PEG are effective in low volume, low frequency dosages andare also surprisingly palatable so that patients are far more compliantwith their treatment regimens and results are significantly improved.

Polyethylene glycols useful in the composition of the invention broadlycomprise any food-grade or pharmaceutical-grade PEG. Currently preferredfor convenience of use in preparing and using the composition of theinvention are polymers having molecular weights above about 900 whichare solid at room temperature and soluble in or miscible with water.Polymers having average molecular weights between about 3000 and 8000are exemplary; PEG 4000, which is nearly odorless and tasteless andwidely available in USP grade, or PEG 3350, are very suitable. These andother suitable PEG powders are commercially available, from, forexample, Spectrum Chemical Mfg. Company, Gardena, Calif. A proprietarylaxative, MiraLax® (Braintree Laboratories, Braintree, Mass.) is auseful source of PEG 3350 powder readily soluble in water. Non-powderedPEG should be comminuted to a particle size that is readilysoluble/miscible in water before use. Lower molecular weight polymerssuch as PEG 400 which are liquid at room temperature may also be used inthe practice of the invention, however, they are not generally expectedto be as satisfactory as higher molecular weight PEGs. PEG compositionswithout added electrolytes such as found in Colyte® (Schwartz Pharma,Milwaukee) and other proprietary PEG-based bowel lavages, are preferredfor their better taste.

Lactulose for the practice of the invention is readily availableover-the-counter. A convenient and relatively tasteless formulation,often referred to in the trade as “lactulose powder for oral solution”can be obtained, for example, from Bertek Pharmaceuticals, Sugarland,Tex. as Kristalose® in 10 and 20 gm packets. The lactulose syrupscommonly sold as laxatives such as Cephulac®, Chronulac®, Cholac®, andEnulose® are not preferred in the practice of the present inventions asseveral contain undesirable additives and many patients object to theirtaste. However, such syrups can be substituted for lactulose powder byusing sufficient syrup to provide the desired dosage of lactulose;typically, the named syrups contain about 10 gm lactulose in 15 ml ofsyrup.

PEG and lactulose are each prepared as described above, conveniently aspowders, for ready solubility/dispersability in water or other aqueousliquid such as juice to provide a palatable drink for liquidadministration. If a PEG/lactulose composition is desired, the powdersare then combined to form a dry composition and, for use, dissolved inthe selected liquid. The PEG and lactulose components are typicallycombined in proportions of from about 0.15 to 3.5 parts by weight PEG to1 part by weight lactulose; in many cases, a range of from about 0.5 to2 or 0.5 to 3 parts by weight of PEG to 1 part by weight lactulose willbe effective. If the PEG to lactulose ratio is too low, the side effectsof the lactulose will become pronounced and compliance will drop off; ifthe PEG to lactulose ratio is too high, the volume of composition whichmust be ingested to obtain the benefits of the lactulose component maybe undesirably high and the excess of PEG may exacerbate or precipitateundesirable side effects. Individual dosages will usually range fromabout 5 to 35 gm PEG and from about 10 to 30 gm lactulose powder (ormore if it is indicated and can be tolerated). In mild-to-moderate ormoderately severe cases of HE from about 10 to 20 gm PEG to about 10 to20 gm lactulose is recommended as a starting dosage. In a particularexample, about 10 gm powdered lactulose such as Kristalose® is admixedwith about 17 gm powdered PEG 3350 (Spectrum Chemical Mfg. Company,Gardenia, Calif.) to provide a dry lactulose/dry PEG compositionaccording to the invention comprising 1.7 parts by weight PEG to 1 partby weight lactulose, to be taken diluted with water or other water-basedliquid to taste.

For use, the dry lactulose/dry PEG composition, with or without optionalconventional additives such as electrolytes coloring matter, orflavorings, is dispersed/dissolved in sufficient water or other aqueousmedium to formulate a relatively smooth, palatable drink. Single dosagesof dry composition containing from about 5 to 35 gm of PEG, for example,about 17 gm, admixed with about 10 to 30 gm lactulose, for example about10 gm, are conveniently dispersed/dissolved in from about 6 to 10 fl.oz., conveniently about 8 fl. oz., of water or other palatablewater-based liquid such as juice, to provide a low-volume drink for oraladministration. About two tablespoons of a dry lactulose/PEG compositionaccording to the invention dissolved in about 8 fl. oz. of water andadministered from about 1 to 3 times a day, usually 2 times a day, willgenerally provide satisfactory results. The volume of water or otherliquid in which the dry composition is dissolved/dispersed is notcritical; in fact, two to three or more extra glasses of water or otherliquid in conjunction with each drink may be generally beneficial. Thedosages can be administered once or twice a day or more if indicated(e.g., tid or qid) until HE symptoms have abated. Results achievedinclude alleviation of constipation with bowel movements from 2-4 timesper day and reduction of toxic plasma ammonia levels by about 25% to 50%or more to clinically-acceptable stable levels.

The product has a relatively rapid response time of from one to abouttwo days. A maximum response can be expected in from one to two weeks,with the response continuing on this plateau with continued use of theproduct. The product is not habit forming, and can be administered asneeded or on a continuing basis for many weeks, months, or years,usually without significant problem. Dosages can be increased ordecreased, or PEG or lactulose concentration increased or decreased tomodulate results according to medical necessity. For example, moderateto heavy diarrhea may be initially desirable if, for example, HE hasbeen precipitated by excessive protein intake, to flush nitrogenouscompounds from the bowel before they are degraded to ammonia: in thiscase, an increase in the number of dosages per day may be helpful as maybe an increase in PEG concentration in the dosage formulation, or both.Conversely, if for example, constipation has been substantiallyalleviated but ammonia levels remain undesirably high, an increase inthe lactulose concentration of the dosage formulation may be helpful. Insome cases, such as severe HE requiring hospitalization, it may bedesirable to administer the PEG dosage separately from the lactulosedosage, as by alternating the selected amount of lactulose with theselected amount of PEG two or more times daily.

In preferred embodiments of the invention, gut microbiota are used inconjunction with the compositions and methods of the present inventionsto enhance ammonia reduction and to promote normalization of indigenousintestinal microbial flora colonies disrupted by, for example, diseasesor other disorders or by ingestion of flora-toxic substances, notablyantibiotics.

The therapeutic potential of gut microbiota is well-recognized, butexploitation is in its infancy. In general, the microbiota include“probiotics”, comprising live microbial strains; “prebiotics”, whichselectively stimulate gut-beneficial microbes; and “symbiotics”,comprising mixtures of probiotics and prebiotics. Prerequisites foruseful gastrointestinal microbiota include non-pathogenicspecies-specific native microbes at-home in the host intestinal tract,preferably having a prolonged shelf-life. The predominant native humangut genera include Bacteriodes, Lactobacillus, Clostridium,Fusobacterium, Bifidobacterium, Eubacterium, Peptococcus,Peptostreptococcus, Escherichia, and Veillonella. Preferred therapeuticbeneficial strains bifidobacteria and lactobacilli; both are lactic acidbacteria. Selected strains may be admixed for use.

Extended discussions of suitable probiotic microorganisms and theirroles in gastrointestinal health are found, for example, in J. Nutri.130:3965, 2000 (“The Role of Probiotic Cultures in the Control ofGastrointestinal Health”, R. D. Rolfe) and Calcut Medical Journal 4:e32006 (“Probiotics in Humans-Evidence-based Preview”, K Harish et al).Both of these publications are incorporated by reference herein.

Many of these microbiota are commercially available; the lactic acidbacteria can routinely be found in health food stores or on theInternet. Recommended dosages are supplied by product inserts and/or inthe literature. The microbiota can be included in the compositions ofthe invention, or administered in conjunction with the lactose/PEGcompositions.

In an alternate mode of practice according to the invention, powderedlactulose may be combined with liquid PEG (polyethylene glycol polymerwhich is liquid at room temperature) or dissolved powdered PEG.Proportions for a suitable liquid PEG/lactulose composition comprise,for example, about 10 to 20 gms powdered lactulose in 8-10 fl. oz. ofPEG. If desired, the liquid PEG/lactulose composition may be furtherdiluted with water for oral administration; for this application, PEGsoluble in or miscible with water at room temperature is much preferred.Diluted or undiluted, the liquid or liquified PEG/lactulose compositionis conveniently administered orally, in a regimen as described above fora diluted dry lactulose PEG composition. The liquid compositions oflactulose syrup and PEG powder mentioned above can be similarlyprepared, admixing for example from about 15 to 30 ml syrup containing10 g lactulose/15 ml of syrup with from about 10 to 20 gm powdered PEG;this composition may also be diluted as desired for oral administrationas described above. If desired, a suitable wetting agent is added to anyof the liquid lactulose/PEG compositions to promote dispersal/dissolvingof the dry matter in the liquid to make a reasonably smooth andpalatable drink.

As previously noted, PEG in either powdered or liquid form can beefficacious alone, particularly in milder cases of HE. In this mode ofpracticing the invention, individual dosages of PEG in amounts of fromabout 5 to 35 gm, especially from 10 to 20 gm, powder or from about 8-10fl. oz. liquid are administered to HE patients whose plasma ammonialevels require reduction, in amounts sufficient to effect this reductionin the regimens described supra for PEG/lactulose compositions, e.g., 1to 3 times daily.

In practice the inventions described herein can provided a good clinicalresponse with substantial resolution of both cognitive and physicalsymptoms of HE such as confusion and asterixis. Importantly, theinventions permit HE patients in many cases to maintain themselves on arestricted protein diet (30-40 g protein daily), without significantrecurrence of HE.

The following Examples are illustrative of making, using, and practicingthe invention.

EXAMPLE

The patient is a 78 year old female with cryptogenic cirrhosis, a typeof cirrhosis which has unknown etiology. She has had extensive workupsfor chronic anemia in one of the major California hospitals and wasplaced on neomycin, Lasix, iron sulfate, lactulose, and Prevacid; shealso was on a restricted protein diet to reduce ammonia production. Shehad intermittent episodes of hepatic encephalopathy during herhospitalization. The patient's hemoglobin slowly drops and she requirestransfusions periodically because of portal gastropathy. The patient'sammonia levels are high, for which she takes lactulose up to three tofour times a day; she has three to four to five bowel movements per day.The patient has a difficult time taking lactulose because of the nausea,abdominal discomfort, and bloating sensation she gets with the drug andits unpleasant taste. Although the therapeutic range is three to fourbowel movements per day, it is very difficult for her to get to thatrange because of these effects.

The patient has required several hospitalizations for lethargy, declinesin hemoglobin, and hepatic encephalopathy. She has intermittent episodesof abdominal discomfort and mild irritation of various small bowelloops.

Laboratory data shows creatinine at 1.5, albumin at 2.6, total bilirubinat 1.17, and hemoglobin in the 9 to 10-range constantly declining andrequiring transfusions periodically. The platelet count is in the rangeof 57,000. The lowest level of ammonia has been 30 micromoles/L andseveral levels have been 80 to 90 micromoles/L with the patient takingthe lactulose.

The patient has had three hospitalizations for hepatic encephalopathyand anemia, mostly resulting from poor compliance. The patient's lasthospitalization was July 22nd. Four months later, the patient presentedus with hepatic encephalopathy and bedsores.

She was switched to 17 g MiraLax® (PEG 3350 powder) combined with 10 gof lactulose dissolved in water and given twice a day. The patient'sammonia level is now in the 70 to 75-range of micromoles/L and holdingfairly steady on a maintenance dosage of this composition once per day.

The patient is now alert and oriented with no tremor or asterixis or anysigns of hepatic encephalopathy. The patient is more compliant andaccepts the taste and does not get the bloating and nausea and crampysensations associated with lactulose. She has achieved clinical andtherapeutic levels of ammonia levels, and is oriented to time and place,with no clinical signs of hepatic encephalopathy on physicalexamination.

1. A pharmaceutical composition for the treatment or prevention ofhyperammonemia comprising PEG and lactulose in an amount from about 0.5to 3 parts by weight polyethylene glycol (PEG) to about 1 part by weightlactulose.
 2. A single dosage of the composition of claim 1 comprisingabout 5 to 35 gm of PEG.
 3. The single dosage composition of claim 2,comprising about 10 to 30 gm of lactulose.
 4. The single dosagecomposition of claim 3, comprising about 10 to 20 gm PEG and 10 to 20 gmlactulose.
 5. A composition according to claim 1, wherein the PEG issolid at room temperature.
 6. A composition according to claim 3,wherein the PEG is solid at room temperature.
 7. A composition accordingto claim 1, wherein the lactulose and PEG are each a dry powder.
 8. Acomposition according to claim 3, wherein the lactulose and PEG are eacha dry powder.
 9. A composition according to claim 4, wherein thelactulose and PEG are each a dry powder.
 10. A composition according toclaim 1, wherein the composition is free of serum electrolytes.
 11. Acomposition according to claim 3, wherein the composition is free ofserum electrolytes.
 12. The composition of claim 1, wherein the patienthas, or is at risk of, HE characterized by hyperammonemia.
 13. Thecomposition of claim 3, wherein the patient has, or is at risk of, HEcharacterized by hyperammonemia.
 14. A pharmaceutical compositionaccording to claim 1, wherein the composition further includes at leastone probiotic or prebiotic or a mixture thereof.
 15. The composition ofclaim 14, wherein the composition comprises at least one probioticselected from Bacteriodes, Lactobacillus, Clostridium, Fusobacterium,Bifidobacterium, Eubacterium, Peptococcus, Peptostreptococcus,Escherichia, and Veillonella.
 16. The composition of claim 15, whereinat least one probiotic is a strain of Lactobacillus or Bifidobacteriumor a mixture thereof, and at least one prebiotic, if present, is astimulant for the selected strain or strains.
 17. A method for thetreatment of a patient with hyperammonemia, comprising orallyadministering to the patient a pharmaceutical composition free of serumelectrolytes and comprising from about 0.15 to 3.5 parts by weight PEGto about 1 part by weight lactulose and at least one probiotic orprebiotic, or a mixture thereof, in an amount and frequency sufficientto reduce patient plasma ammonia to a clinically-acceptable level or tomaintain this level, or both.
 18. The method of claim 17, wherein thecomposition comprises from about 0.5 to 3 parts by weight PEG to 1 partby weight lactulose.
 19. The method of claim 17, wherein the compositionis administered in single dosages each comprising about 5 to 35 gm ofdry PEG dissolved in the aqueous carrier.
 20. The method of claim 19,wherein each single dosage further comprises about 10 to 30 gm of drylactulose dissolved in the aqueous carrier.
 21. The method of claim 20,wherein each single dosage comprises about 10 to 20 gm PEG and about 10to 20 gm lactulose dissolved in the aqueous carrier.
 22. The method ofclaim 17, wherein the composition is a dry composition formulated as aliquid drink by admixture with a pharmaceutically-acceptable aqueouscarrier.
 23. The method of claim 17, wherein the composition comprisesat least one probiotic selected from Bacteriodes, Lactobacillus,Clostridium, Fusobacterium, Bifidobacterium, Eubacterium, Peptococcus,Peptostreptococcus, Escherichia, and Veillonella.
 24. The composition ofclaim 23, wherein at least one probiotic is a strain of Lactobacillus orBifidobacterium or a mixture thereof, and at least one prebiotic, ifpresent, is a stimulant for a selected strain or strains.